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Methanolobus halotolerans strain:SY-01

ABSTRACT: Methanolobus halotolerans strain:SY-01 Genome sequencing and assembly

PROVIDER: PRJNA417540 | ENA |

REPOSITORIES: ENA

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Project description:Recent studies reveal that a subset of cancers in various indications are dependent on high and constant expression of certain transcription factors for growth and survival, a phenomenon termed as transcriptional addiction. Therefore, targeting transcriptional machinery can potentially lead to potent and selective anticancer effects. CDK7 is the catalytic subunit of the CDK-activating kinase (CAK) complex. Its function is required for both cell cycle regulation and transcriptional control of gene expression. CDK7 has recently emerged as an attractive target in cancer since its inhibition leads to decrease of the transcript levels of oncogenic transcription factors, especially those associated with super-enhancers (SEs). Here we describe a first-in-class CDK7 inhibitor SY-1365, which covalently targets a cysteine outside the kinase domain, resulting in sustained, highly selective inhibition of CDK7. In vitro studies reveal that SY-1365 has potency in a wide range of cancer models with low micromolar IC50 values. Cancer cells with low BCL-XL expression are found to be more dependent on MCL1 for survival and therefore particularly sensitive towards SY-1365 treatment since SY-1365 downregulates MCL1 protein level. SY-1365 treatment induces distinct transcriptional changes in acute myeloid leukemia (AML) cell lines. SY-1365 also demonstrates substantial anti-tumor effects in multiple AML xenograft models. Additionally, combination treatment with venetoclax shows synergistic effects in AML models both in vitro and in vivo. Our findings support targeting CDK7 as a new approach for treating transcriptionally addicted cancers. SY-1365 is currently being assessed in a Phase I trial in adult patients (NCT03134638) We performed microarray based expression profiling to quantify transcriptional changes upon treatment with the CDK7 inhibitor, SY-1365 and to compare it to transcriptional changes induced by treatment with other transcriptional drugs JQ1 (BRD4 inhibitor), NVP2 (CDK9 inhibitor) and flavopiridol (pan-CDK inhibitor). We profiled a human acute myeloid leukemia (AML) cell line THP-1. Cells were treated with either DMSO, 100nm SY-1365, 25nM NVP2 , 250nM JQ1 or 200nM flavopiridol for two and six hours. All samples were prepared in biological triplicate.

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Methanolobus halotolerans strain:SY-01

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